: Type I diabetes mellitus (T1DM) is an autoimmune disease thought to be caused by a T cell mediated destruction of the insulin producing beta cells in the islets of Langerhans. Studies in animal models and limited human clinical studies demonstrate that modulation of T cell responses can alter the natural history of diabetes, but none of the currently available immune suppressive treatments induce a permanent remission of the disease. Animal studies, however, suggest that anti-CD3 monoclonal antibody (mAb) can reverse diabetes and induce long term tolerance to recurrent autoimmunity. This application is for a Phase I/II trial of a new anti-CD3 mAb, hOKT3gamma1 (Ala-Ala) for treatment of new onset (T1DM). This mAb is a humanized form of OKT3 that does not bind the FcR receptor and thus, will not cause the cytokine release syndrome or development of neutralizing antibodies that preclude use of OKT3 in otherwise healthy patients with T1DM. These and other studies in mice suggest that the reagent can selectively inhibit previously activated cells that produce Th1 cytokines thought to be involved in diabetes. The aims of this phase I/II trial are to test the safety, tolerability, and immune effects of hOKT3gamma1(Ala-Ala). The investigators have designed their application to have sufficient statistical power to test whether treatment with the drug will alter the natural history of beta-cell destruction in T1DM. They will study the effects of the drug on depletion of peripheral T cells, activation of T cells using cellular approaches, T cell proliferative responses to common antigens, and stimulation of anti-Ig responses. They will also study the effects of the drug on diabetes specific immune responses including the titer and isotype of autoantibodies and cellular responses, including cytokine production, to islet antigens such as IA-2. They will compare the effects of the mAb on these responses, thought to be of a Th/Tc1 phenotype to responses to common allergens, which are of a Th2 phenotype. The hypothesis to be tested in this Project is that non-FcR binding mAb will inhibit islet antigen reactive Th1 cells that mediate the destruction of beta cells, and thereby alter the natural history of T1DM. Their studies will test a new immunologic approach to treatment that is based on the current understanding of the natural history of diabetes. As a result of these studies, future studies will be of broader scope with a focus on clinical efficacy of non-FcR binding anti-CD3 therapy.